Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists

Brian W Budzik; Karen A Evans; David D Wisnoski; Jian Jin; Ralph A Rivero; George R Szewczyk; Channa Jayawickreme; David L Moncol; Hongshi Yu

doi:10.1016/j.bmcl.2010.01.003

Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists

Bioorg Med Chem Lett. 2010 Feb 15;20(4):1363-7. doi: 10.1016/j.bmcl.2010.01.003. Epub 2010 Jan 7.

Authors

Brian W Budzik¹, Karen A Evans, David D Wisnoski, Jian Jin, Ralph A Rivero, George R Szewczyk, Channa Jayawickreme, David L Moncol, Hongshi Yu

Affiliation

¹ Discovery Medicinal Chemistry, Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA.

PMID: 20097073
DOI: 10.1016/j.bmcl.2010.01.003

Abstract

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.

MeSH terms

Acrylamides / chemical synthesis*
Acrylamides / chemistry
Acrylamides / pharmacology
Drug Design*
Humans
Isoxazoles / chemical synthesis*
Isoxazoles / chemistry
Isoxazoles / pharmacology
Molecular Structure
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Acrylamides
GPBAR1 protein, human
Isoxazoles
Receptors, G-Protein-Coupled